Renal dysfunction or failure and, in particular, end-stage renal disease, causes the body to lose the ability to remove water and minerals and excrete harmful metabolites, maintain acid-base balance and control electrolyte and mineral concentrations within physiological ranges. Toxic uremic waste metabolites including urea, creatinine, and uric acid accumulate in the body's tissues which can result in a person's death if the filtration function of the kidney is not replaced.
Dialysis is commonly used to replace kidney function by removing these waste toxins and excess water. In one type of dialysis treatment—hemodialysis (HD)—toxins are filtered from a patient's blood externally in a hemodialysis machine. Blood passes from the patient through a dialyzer separated by a semi-permeable membrane from a large volume of externally-supplied dialysate. Typically, the blood passes through the inside of semi-permeable hollow fibers, and the dialysate flows on the outside of the semi-permeable hollow fibers in a countercurrent direction. The waste and toxins dialyze out of the blood through the semi-permeable membrane into the dialysate, which is then discarded.
The patient's blood is exposed to intravenous cannulas, tubing, drip chambers, headers, potting compound, and dialysis membranes during the dialysis procedure. These surfaces exhibit a variable degree of thrombogenicity and may initiate clotting of blood, especially in conjunction with exposure of blood to air in drip chambers. The resulting thrombus formation may be significant enough to cause occlusion and malfunction of the extracorporeal circuit. See J. T. Daugirdas, P. G. Blake, and T. S. Ing, Handbook of Dialysis, (2007).
One method of preventing blood clotting is to administer heparin to the patient, shortly before or during the dialysis treatment. Heparin, however, has potential undesirable side effects, such as, for example, pruritus, allergy, osteoporosis, hyperlipidemia, thrombocytopenia, and excessive bleeding. Heparin is therefore not recommended for patients at risk of bleeding due to gastrointestinal lesions (gastritis, peptic ulcer, angiodysplasia), recent surgery, or pericarditis.
Another method of preventing blood clotting is regional citrate anticoagulation (RCA), which can be used alone or combined with and potentially reduce heparin administration. RCA has been shown to reduce complement activation, degranulation of granulocytes and platelets and the release of IL-1b, thus improving biocompatibility of the extracorporeal circuit. Bohler J., Schollmeyer P., Dressel B., Dobos G., Horl W. H.: Reduction of granulocyte activation during hemodialysis with regional citrate anticoagulation: dissociation of complement activation and neutropenia from neutrophil degranulation. J Am Soc Nephrol 7:234-241. 1996; Gabutti L., Ferrari N., Mombelli G., Keller F., Marone C.: The favorable effect of regional citrate anticoagulation on interleukin-1 beta release is dissociated from both coagulation and complement activation. J Nephrol 17:819-825. 2004; Gritters M., Grooteman M. P., Schoorl M., Schoorl M., Bartels P. C., Scheffer P. G., Teerlink T., Schalkwijk C. G., Spreeuwenberg M., Nube M. J.: Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrol Dial Transplant 21:153-159. 2006. The actual anticoagulative effect of RCA in the dialyzer has also been demonstrated to be superior to both unfractionated and low-molecular-weight heparin. Hofbauer R., Moser D., Frass M., Oberbauer R., Kaye A. D., Wagner O., Kapiotis S., Druml W.: Effect of anticoagulation on blood membrane interactions during hemodialysis. Kidney Int 56:1578-1583. 1999. More recently, the sharp rise of heparin costs has further spurred interest in RCA as an alternative mode of anticoagulation.
The application of regional citrate anticoagulation (RCA) in hemodialysis classically involves citrate infusion before the hemodialyzer, calcium infusion after the dialyzer, and use of a calcium-free dialysate. The extremely low ionized calcium (iCa) levels generated by infusion of citrate into the arterial line prevent clotting in the extracorporeal circuit but have to be raised again in the venous line before the blood re-enters the patient's systemic circulation. Citrate infusion and calcium infusion have to be balanced carefully in order to avoid systemic hypo- or hypercalcemia in the patient. See U.S. application Ser. No. 12/580,803, filed on Oct. 16, 2009. This requires close monitoring of systemic iCa levels, which is classically accomplished by repetitive blood draws and iCa measurements throughout the dialysis treatment. This is a labor- and material-intensive process.
An attempt to provide heparin-free anticoagulation without the need for citrate infusion and calcium infusion by employing a commercially available dialysate containing both calcium and citrate (Citrasate® citrate dialysate) resulted in clotting of the hemodialyzer in 2 out of 10 cases in one study. Dittrich et al. J Am Soc Nephrol 19 (2008), page 461A, abstract F-PO1576. This demonstrates that Citrasate® citrate dialysate alone does not provide sufficient anticoagulation, which can be ascribed to the iCa concentration along the hollow fibers not being below the level required for adequate anticoagulation.
Therefore, there is a need for a method of preventing blood clotting during a dialysis treatment of a patient that reduces or eliminates the problems described above.